The proposal deals with specific neuronal mechanisms in the hippocampus responsible for triggering shaking behavior in rats. This behavior is of interest in pharmacology because it is elicited by physchoactive compounds including met-enkephalin and mescaline. In addition, shaking behavior is a prominent sign in opiate abstinence. Our preliminary work indicates that, in awake unrestrained rats, shaking indistinguishable from that induced with drugs can be elicited by electrical stimuli that activate granule cells in the hippocampus. Our hypothesis is that shakes associated with morphine withdrawal and with acute reactions to met-enkephalin and mescaline are mediated by a particular drug effect on hippocampal neurons. The proposal aims include a study of granule cell field potentials in response to perforant path stimuli. Changes in field potentials (amplitude of field EPSP, population spike, twin pulse inhibition) will be the criteria for analyzing the actions of drugs on the hippocampus. Graded doses of met-enkephalin (injected into the cerebroventricles) or of mescaline will be evaluated for their effects on shaking behavior, threshold for analgesia, and hippocampal neuron activity. Hippocampal responses will also be studied in conjunction with shakes precipitated by naloxone in morphine-dependent rats. The specificity for hippocampal sites of action for the drugs will be tested with kainic acid. Kainate lesions, CA3 pyramidal cells, the main output neurons of the hippocampus. The neurotoxin inhibits shakes evoked by electrical stimuli, but it remains to be seen if it blocks the response to shake-inducing drugs. Finally, naloxone will be used to determine whether shaking behavior provoked by electrical stimuli or by opiate withdrawal is mediated by an endogenous opioid. This proposal offers a novel approach for correlating neuronal electrophysiology with a specific mammalian behavior. Information on neuronal mechanisms mediating an identified withdrawal sign will provide opportunities for a comprehensive description of a specific neurotoxicity that evolves from drug dependency. The neuronal mechanisms may also be relevant to processes involved in pain perception.